Manufacture of trimethylhydroquinone diacylates

ABSTRACT

A process for the manufacture of 2,3,5-trimethylhydroquinone diacylate comprising reacting ketoisophorone with an acylating agent in the presence of a NH- or CH-acidic catalyst, particularly certain bis(perfluorinated hydrocarbyl sulphonyl) imides and metal salts thereof and, respectively, certain tris(perfluoroalkanesulphonyl or pentafluorobenzenesulphonyl) methanes and metal salts thereof. The acylating agent is particularly an acid anhydride, an acyl halide or an enol ester. The so-obtained 2,3,5-trimethylhydroquinone diacylate can be converted into (all-rac)-α-tocopherol by transesterification to yield 2,3,5-trimethylhydroquinone and reaction of the latter with isophytol. (all-rac)-α-Tocopherol itself is the most active member of the vitamin E group.

This application is the National Stage of International Application No.PCT/EP02/13890, filed Dec. 7, 2002.

The present invention is concerned with a process for the manufacture of2,3,5-trimethylhydroquinone diacylates by reacting ketoisophorone withan acylating agent in the presence of a so-called NH- or CH-acidiccatalyst. The products of the process are useful as reactants for themanufacture of 2,3,5-trimethylhydroquinone, itself a known valuablereactant for the manufacture of (all-rac)-α-tocopherol, the most activemember of the vitamin E group.

2,3,5-Trimethylhydroquinone diacylates are known to be producible byreacting ketoisophorone with an acylating agent in the presence of astrongly acidic catalyst. Many such catalysts have been proposed in thepast for this purpose, in particular protonic acids, e.g. such inorganicacids as sulphuric acid; such organic acids as p-toluenesulphonic acid;strongly acidic ion exchange resins; and such Lewis acids as zincchloride, boron trifluoride, antimony pentafluoride and titaniumtetrachloride: see inter alia German Offenlegungsschrift 2149159 andEuropean Patent Publications EP 0916642 A1 and EP 1028103 A1. Inaccordance with the present invention it has been found that theconversion of ketoisophorone to 2,3,5-trimethylhydroquinone diacylatescan be advantageously accomplished by the use of NH-acidic or CH-acidiccatalysts, especially those which have been found to be useful catalystsfor the condensation of 2,3,5-trimethylhydroquinone with isophytol toyield α-tocopherol, as described in PCT Publication WO 98/21197 andEuropean Patent Publications EP 1180517 A1 and EP 1134218 A1. Advantagesof such catalysts used in the process in accordance with the presentinvention are the avoidance of corrosion, the avoidance of waste watercontamination with heavy metal ions and the high selectivity.

Accordingly, the present invention provides a process for themanufacture of a 2,3,5-trimethylhydroquinone diacylate, which processcomprises reacting ketoisophorone with an acylating agent in thepresence of a NH-acidic catalyst, especially one of the general formula[(R¹SO₂)₂N]_(x)R²  (I)or a CH-acidic catalyst, especially one of the general formula[(R³SO₂)₃C]_(x)R²  (II)wherein each of R¹, independently, signifies a perfluoroalkyl groupC_(n)F_(2n+1) or pentafluorophenyl, or both symbols R¹ together signifya poly-difluoromethylene group —(CF₂)_(m)—,

-   R² signifies a proton or a metal cation selected from the group    consisting of boron, magnesium, aluminium, silicon, scandium,    titanium, vanadium, manganese, iron, cobalt, nickel, copper, zinc,    yttrium, zirconium, rhodium, palladium, silver, tin, lanthanum,    cerium, praseodymium, neodymium, europium, dysprosium, thulium,    ytterbium, hafnium, platinum and gold cations,-   each of R³, independently, signifies a perfluoroalkyl group    C_(n)F_(2n+1) or pentafluorophenyl,-   m signifies an integer from 2 to 4,-   n signifies an integer from 1 to 10 and-   x signifies an integer from 1 to 5 corresponding to the valency of    the proton (1) or the metal cation (1, 2, 3, 4 or 5) signified by    R².

Examples of the cations signified by R² in both formulae above, usingtheir chemical symbols, are B³⁺, Mg²⁺, Al³⁺, Si⁴⁺, Sc³⁺, Ti⁴⁺, V³⁺, V³⁺,Mn²⁺, Mn⁴⁺, Fe²⁺, Fe³⁺, Co²⁺, Ni²⁺, Cu⁺, Cu²⁺, Zn²⁺, Y³⁺, Zr⁴⁺, Rh³⁺,Pd²⁺, Ag⁺, Sn⁴⁺, La³⁺, Ce³⁺, Pr³⁺, Nd³⁺, Eu²⁺, Dy³⁺, Tm³⁺, Yb³⁺, Hf⁴⁺,Pt²⁺and Au³⁺.

Not only some of the above-defined NH-acidic catalysts of the formula Iwherein R² signifies a proton [all being bis(perfluorinated hydrocarbylsulphonyl)imides] but also some of their metal salts amongst thecatalysts of formula I are known compounds. Those catalysts of formula Iwhich may still not be known can be produced by methods analogous to thepublished methods for producing bis(trifluoromethylsulphonyl)imide andits metal salts and the higher members of these sulphonimides and theirmetal salts: see, for example, EP 364340/U.S. Pat. No. 5,256,821,Japanese Patent Publications (Kokai) 246338/1995, 064238/1996 (with theUS counterpart U.S. Pat. No. 5,650,244), 057110/1997, 169690/1997,176063/1997, 176171/1997, 241184/1997, 230166/1998, 330314/1998 and209338/1999, DOS 4217366/U.S. Pat. No. 5,502,251, DOS 19533711/U.S. Pat.No. 5,723,664, Chemiker Zeitung 96, 582–583 (1972), Chem. Lett. 1995,307–308, Synlett 1996, 171–172, 265–266 and 839–841, Inorg. Chem. 35(7),1918–1925 (1996), J. Power Sources 68, 307–310 (1997) and Cat. Today36(1), 81–84 (1997) as well as the further literature referencesmentioned in this state of the art. For example, many of the salts canbe produced from the appropriate bis(perfluorinated hydrocarbylsulphonyl)imide of formula I in which R² signifies a proton and themetal acetate, oxide, hydroxide or alcoholate featuring the desiredmetal cation. In the case of the aluminium, zinc and various other metalsalts these can also be produced using the corresponding alkylmetal ordialkylmetal hydride, e.g. diethylzinc or triethylaluminium or,respectively, diisobutylaluminium hydride.

In some cases the metal salts can be present in monomeric or polymericform and, accordingly, formula I is intended to embrace all such forms.Further, these catalysts can be used in isolated form or produced insitu.

Examples of a catalyst of formula I in which the symbols R¹ togethersignify a poly-difluoromethylene group —(CF₂)_(m)— are4,4,5,5,6,6-hexafluoro-(1,3,2)dithiazinane-1,3-dioxide and its silversalt.

Some of the CH-acidic catalysts of the formula II wherein R² signifies aproton and their metal salts are known compounds. Thus in Inorg. Chem.27, 2135–2137 (1988) K. Seppelt and L. Turowsky describe for the firsttime the preparation of tris(trifluoromethanesulphonyl)methane,(CF₃SO₂)₃CH, and of four salts thereof, viz. the potassium, rubidium,silver and cesium salts. The lithium and further metal salts of(CF₃SO₂)₃CH and other tris(perfluoroalkanesulphonyl)methides and theirpreparation are described in U.S. Pat. No. 5,273,840. Also developingthe original work of Seppelt and Turowsky, F. J. Waller et al. describein J. Org. Chem. 64, 2910–2913 (1999) the further preparation of(CF₃SO₂)₃CH and its cesium salt, and also the preparation of thecorresponding scandium and ytterbium salts. In Synlett 1999, No. 12,1990–1992, J. Nishikido et al. describe the preparation of scandium,yttrium and, in general, lanthanide (III)tris(perfluorobutanesulphonyl)methide complexes. Further literatureconcerning the preparation of these and further metaltris(perfluoroalkanesulphonyl)methides includes U.S. Pat. No. 5,554,664and the many references mentioned in this and in other aforementionedpublications.

The tris(perfluoroalkanesulphonyl orpentafluorobenzenesulphonyl)methanes or metal salts thereof embraced bythe formula II hereinbefore and used as the catalysts in the process ofthe present invention can be produced according to such publishedmethods or, in the case of those methanes or metal salts thereof whichmay still not be known, according to analogous methods.

Preferred NH- and CH-acidic catalysts for use in the process of thepresent invention are those NH-acidic catalysts of the formula I whereineach of R¹ signifies trifluoromethyl or pentafluoroethyl, or bothsymbols R¹ together signify perfluoro-1,3-propylene, especially thosewherein in addition R² signifies a proton; and those CH-acidic catalystsof the formula II wherein each of R³ signifies trifluoromethyl,especially those wherein in addition R² signifies a proton or a divalentnickel cation.

The acylating agent used in the process of the present invention may beany acylating agent that is conventionally used in the conversion ofketoisophorone to 2,3,5-trimethylhydroquinone acylates, particularlyacid anhydrides, acyl halides, and enol esters. Examples of acidanhydrides are straight or branched chain alkanoic acid anhydrides suchas acetic, propionic and butyric anhydride. Examples of acyl halides arestraight or branched chain alkanoyl chlorides such as acetyl, propionyland butyryl chloride. Finally, examples of enol esters are isopropenylacetate and butyrate. The preferred acylating agent is acetic anhydrideor acetyl chloride, especially acetic anhydride.

The process of the present invention can be carried out in the presenceor in the absence of a solvent. As a solvent, any inert polar ornon-polar organic solvent or any mixture of two or more of such solventscan be used. Suitable classes of polar organic solvents includealiphatic and cyclic ketones, e.g. diethyl ketone and isobutyl methylketone and, respectively, cyclopentanone and isophorone; and aliphaticand cyclic esters, e.g. ethyl acetate and isopropyl acetate, and,respectively, γ-butyrolactone, ethylene carbonate and propylenecarbonate. As suitable classes of non-polar organic solvents there maybe mentioned aliphatic hydrocarbons, e.g. hexane, heptane and octane,and aromatic hydrocarbons, e.g. benzene, toluene and the xylenes. Thereaction can be effected in a single solvent phase, e.g. in toluenealone as the solvent, or in a biphasic solvent system, e.g. in ethyleneor propylene carbonate and heptane.

While the ratio of acylating agent to ketoisophorone is not narrowlycritical the ratio of acylating agent (equivalents) to ketoisophorone(moles) is suitably from about 1:1 to about 5:1, preferably from about2:1 to about 3:1, and is most preferably about 3:1.

The amount of catalyst of formula I or II used is suitably about 0.1 toabout 2.0 mole %, preferably about 0.5 to about 1.5 mole %, and mostpreferably about 0.8 to about 1.2 mole %, based on the moles ofketoisophorone present.

The process is conveniently carried out at temperatures from about 20°C. to about 60° C., preferably from about 30° C. to about 50° C.

Moreover, the process is conveniently carried out under an inert gasatmosphere, preferably under gaseous nitrogen or argon.

The progress of the reaction is suitably monitored by gas chromatographyand mass spectrometry of samples taken from the reaction mixture atvarious time intervals during the reaction.

The produced 2,3,5-trimethylhydroquinone diacylate can be isolated afterdistilling off the remaining acylating agent and the secondary productformed in the acylation, e.g. acetic acid when acetic anhydride is usedas the acylating agent, by extraction of the crude product mixture witha suitable organic solvent, e.g. toluene. For instance, in effectingthis procedure using acetic anhydride as the acylating agent2,3,5-trimethylhydroquinone diacetate was obtained as colourlesscrystals after evaporating off the toluene used as the extractingsolvent. Another isolation procedure is the crystallization of the2,3,5-trimethylhydroquinone diacylate from the mixture at thetermination of the reaction by cooling, and, optionally, adding water,to the mixture to promote the crystallization.

The catalyst can be recovered by extraction with water or acid-water andconcentration of the extract. Alternatively, the catalyst can berecovered by adding a biphasic solvent system, e.g. a carbonate(particularly ethylene carbonate or propylene carbonate) and analiphatic hydrocarbon (particularly heptane or octane), and isolating itfrom the polar (carbonate) phase

The 2,3,5-trimethylhydroquinone diacylate obtained by the process of thepresent invention can be converted into 2,3,5-trimethylhydroquinone bytransesterification, i.e. by treatment with an alcohol, e.g. analiphatic alcohol such as isopropanol or n-butanol. Depending on theamounts of alcohol and catalyst and on the temperature in the reactionmixture, the transesterification yields the unesterified2,3,5-trimethylhydroquinone and the ester formed as the further product.The former product can be converted into (all-rac)-α-tocopherol byreaction with isophytol, preferably in a biphasic solvent system, e.g.in a solvent system comprising a polar solvent such as ethylene orpropylene carbonate, and an non-polar solvent, particularly an aliphatichydrocarbon such as heptane.

The invention is illustrated by the following Examples.

EXAMPLE 1

To a mixture of 20.28 g (199 mmol) of acetic anhydride and 218.4 mg(0.777 mmol) of bis(trifluoromethanesulphonyl)amine there were added,with stirring, 10.17 g (66.82 mmol) of ketoisophorone within 30 minutesunder a nitrogen flow. After 20 minutes, the temperature rose from about25° C. to about 46° C. The reaction mixture was then held at the highertemperature and the reaction allowed to proceed with stirring for anadditional 2.5 hours. The reaction mixture was found to contain 88% of2,3,5-trimethylhydroquinone diacetate (percentage given as area %according to gas chromatography) and minor amounts of unreactedketoisophorone. The so-obtained product could be worked up bycrystallization at about 4° C., e.g. from hexane, or by distillation.

EXAMPLE 2

The acylation reaction was carried out substantially as described inExample 1. After a reaction time of 3 hours, 3.88 g (about 4.9 ml; 66.88mmol) of isopropanol were added under continuous stirring and nitrogenflow in order to quench the reaction by conversion of the remainingacetic anhydride into acetic acid and isopropyl acetate. The mixture washeated to 90° C. and after 8 hours was concentrated by distillation.2,3,5-Trimethylhydroquinone diacetate was isolated from the mixture bycrystallization at room temperature and filtration.

EXAMPLE 3

The acylation reaction was carried out substantially as described inExample 1. After completion of the acylation the remaining aceticanhydride was removed at 75° C./20 mbar (2 kPa). Then, 25 ml of toluenewere added twice and removed by evaporation after each addition. Theresidue was dried at 60° C./30 mbar (3 kPa). To the so-obtained residuecontaining 15.11 g of crude 2,3,5-trimethylhydroquinone diacetate wereadded 78.48 g (0.8912 mmol) of ethylene carbonate under a nitrogenatmosphere, and the mixture was heated to 90° C. Then 3.88 g (about 4.9ml; 66.88 mmol) of isopropanol were added to the mixture for the samepurpose as in the case of Example 2 above. After 5 hours the reactionmixture was concentrated by distillation and 2,3,5-trimethylhydroquinonediacetate crystallized out at room temperature and could be removed fromthe mixture by filtration. The mother liquor containing the catalyst wasrecycled.

EXAMPLE 4

The acylation reaction was carried out substantially as described inExample 1. After completion of the acylation the remaining aceticanhydride was removed at 75° C./20 mbar (2 kPa). Then, 25 ml of toluenewere added twice and removed by evaporation after each addition. Theresidue was dried at 60° C./30 mbar (3 kPa). To the so-obtained residuecontaining 15.2 g of crude 2,3,5-trimethylhydroquinone diacetate (90%content), there were added 78.48 g (0.8912 mmol) of ethylene carbonateunder a nitrogen atmosphere. This mixture was heated to 100° C. and37.31 g (270 mmol) of isopropanol were then added. After 5 hoursreaction time 120 ml of heptane were added in one quantity, followed by58 mmol isophytol during 30 minutes, the temperature of the reactionmixture being retained at 100° C. To isolate the resulting crude(all-rac)-α-tocopherol the solvent was evaporated under reducedpressure; this yielded 22.9 g of (all-rac)-α-tocopherol.

This Example illustrates a multistep process starting fromketoisophorone and the acylating agent acetic anhydride via thediacetate of 2,3,5-trimethylhydroquinone (not isolated) followed by thetransesterfication with isopropanol to the unesterified2,3,5-trimethylhydroquinone and finally involving the reaction of thelast-named product with isophytol to afford (all-rac)-α-tocopherol. Theexcess amount of isopropanol used serves to saponify the formed2,3,5-trimethylhydroquinone diacetate and to esterify the aceticanhydride, the ratio of isopropanol equivalents used being approximately3:1 for these two purposes.

EXAMPLE 5

In analogy to Example 1, acylation/rearrangement reactions were carriedout using various catalyst and/or other reactions conditions. Theresults are given in the Table below.

Amount of Reaction Reaction KIP TMHQ-DA Catalyst catalyst temperaturetime GC-area % GC-area % (CF₃SO₂)₂NH 1.1 mole % 45° C.* 18 h 6.5 82.7(CF₃SO₂)₂NH 1.1 mole % 45° C. 14 h 1.2 88.0 (CF₃SO₂)₂NH 2.2 mole % 45°C. 5 h 0.2 88.5 (CF₃SO₂)₂NH 2.2 mole % 45° C. 6 h 0.0 88.3 (CF₃SO₂)₂NH1.1 mole % 70° C. 2.5 h 3.7 85.0 (C₂F₅SO₂)₂NH 1.1 mole % 45° C. 8.5 h0.4 88.0 (SO₂CF₂CF₂CF₂SO₂)NH 1.1 mole % 45° C.* 6.5 h 6.1 83.9(SO₂CF₂CF₂CF₂SO₂)NH 1.1 mole % 45° C. 7.5 h 0.0 88.2 (CF₃SO₂)₃CH 1.1mole % 45° C.* 6 h 7.7 82.5 Ni((CF₃SO₂)₃C)₂ 1.1 mole % 45° C. 24.5 h 5.383.9 *cooling to 0–10° C. during KIP addition KIP: ketoisophoroneTMHQ-DA: 2,3,5-trimethylhydroquinone diacetate GC-area %: area percentaccording to gas chromatography

1. A process for the manufacture of a 2,3,5-trimethylhydroquinonediacylate comprising reacting ketoisophorone with an acylating agent inthe presence of a NH- or CH-acidic catalyst.
 2. A process according toclaim 1, wherein the NH-acidic catalyst is a compound of the generalformula[(R¹SO₂)₂N]_(x)R²  (I) and the CH-acidic catalyst is a compound of thegeneral formula[(R³SO₂)₃C]_(x)R²  (II) wherein each of R¹, independently, signifies aperfluoroalkyl group C_(n)F_(2n+1) or pentafluorophenyl, or both symbolsR¹ together signify a poly-difluoromethylene group —(CF₂)_(m)—, R²signifies a proton or a metal cation selected from the group consistingof boron, magnesium, aluminium, silicon, scandium, titanium, vanadium,manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium,rhodium, palladium, silver, tin, lanthanum, cerium, praseodymium,neodymium, europium, dysprosium, thulium, ytterbium, hafnium, platinumand gold cations, each of R³, independently, signifies a perfluoroalkylgroup C_(n)F_(2n+1), m signifies an integer from 2 to 4, n signifies aninteger from 1 to 10 and x signifies an integer from 1 to 5,corresponding to the valency of the proton (1) or the metal cation (1,2, 3, 4, or 5) signified by R².
 3. A process according to claim 2,wherein the catalyst is an NH-acidic catalyst of the general formula Iand each of R¹ therein signifies trifluoromethyl or pentafluoroethyl, orboth symbols R¹ therein together signify perfluoro-1,3-propylene.
 4. Aprocess according to claim 2, wherein R² in the NH-acidic catalyst ofthe general formula I signifies a proton.
 5. A process according toclaim 2, wherein the catalyst is a CH-acidic catalyst of the generalformula II and each of R³therein signifies trifluoromethyl.
 6. A processaccording to claim 2, wherein R² in the CH-acidic catalyst of thegeneral formula II signifies a proton or a divalent nickel cation.
 7. Aprocess according claim 1, wherein the acylating agent is an acidanhydride, an acyl halide or an enol ester.
 8. A process according toclaim 7, wherein the acylating agent is a straight or branched chainalkanoic acid anhydride, a straight or branched chain alkanoyl chloride,or, an enol ester.
 9. A process according claim 1, wherein the ratio ofacylating agent (equivalents) to ketoisophorone (moles) is from about1:1 to about 5:1.
 10. A process according to claim 2, wherein the amountof catalyst of the general formula I or II used is about 0.1 to about2.0 mole %, based on the moles of ketoisophorone present.
 11. A processaccording to claim 1, wherein the acylating reaction is carried out inthe presence of a solvent which is an inert polar or non-polar organicsolvent or any mixture of two or more of such solvents.
 12. A processaccording to claim 11, wherein the polar organic solvent is an aliphaticor cyclic ketone or an aliphatic or cyclic ester, and the non-polarorganic solvent is an aliphatic or aromatic hydrocarbon.
 13. A processaccording to claim 1, wherein the acylating reaction is carried out attemperatures from about 20° C. to about 60° C.
 14. A process accordingto claim 8, wherein the acylating agent is selected from the groupconsisting of acetic anhydride, propionic anhydride, butyric anhydride,acetyl chloride, propionyl chloride, butyryl chloride, isopropenylacetate and isopropenyl butyrate.
 15. A process according claim 9,wherein the ratio of acylating agent (equivalents) to ketoisophorone(moles) is from about 2:1 to about 3:1.
 16. A process according claim15, wherein the ratio of acylating agent (equivalents) to ketoisophorone(moles) is about 3:1.
 17. A process according to claim 10, wherein theamount of catalyst of the general formula I or II used is about 0.5 toabout 1.5 mole %, based on the moles of ketoisophorone present.
 18. Aprocess according to claim 17, wherein the amount of catalyst of thegeneral formula I or II used is about 0.8 to about 1.2 mole %, based onthe moles of ketoisophorone present.
 19. A process according to claim12, wherein the polar organic solvent is selected from the groupconsisting of diethyl ketone, isobutyl methyl ketone, cyclopentanone,isophorone, ethyl acetate, isopropyl acetate, γ-butyrolactone, ethylenecarbonate and proplyene carbonate, and the non-polar organic solvent isselected from the group consisting of hexane, heptane, octane, benzene,toluene and xylene.
 20. A process according to claim 13, wherein theacylating reaction is carried out at temperatures from about 30° C. toabout 50° C.